Positron Emission Tomography is a molecular imaging technology that is increasingly used for detection of disease. PET imaging systems create images based on the distribution of positron-emitting isotopes in the tissue of a patient. The isotopes are typically administered to a patient by injection of probe molecules that comprise a positron-emitting isotope, e.g. carbon-11, nitrogen-13, oxygen-15, or fluorine 18, covalently attached to a molecule that is readily metabolized or localized in the body or that chemically binds to receptor sites within the body. For PET probes the short half-lives of the positron emitters require that synthesis, analysis and purification of the probes are completed rapidly.
Large-volume synthesis modules have been developed and used for the preparation of a number of radiopharmaceutical compounds. Common pharmaceuticals radiolabeled with F-18 include 2-deoxy-2-[F-18]-fluoro-D-glucose (18F-FDG), 3′-deoxy-3′-[F-18]-fluorothymidine (18F-FLT), 9-[4-[F-18] fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG), 9-[(3-[F-18] fluoro-1-hydroxy-2-propoxy)methyl]guanine (18F-FHPG), 3-(2′-[F-18] fluoroethyl)spiperone (18F-FESP), 4-[F-18] fluoro-N-[2-[1-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (18F-p-MPPF), 2-(1-{6-[(2-[F-18]fluoroethyl)-(methyl)amino]-2-naphthyl}ethylidine)malononitrile (18F-FDDNP), 2-[F-18] fluoro-α-methyltyrosine, [F-18] fluoromisonidazole (18F-FMISO), 5-[F-18] fluoro-2′-deoxyuridine (18F-FdUrd). Other common radiolabeled compounds include 11C-methionine and 11C-acetic acid. Large volume synthesis modules occupy a large amount of space and the chemical process requires longer reaction time cycles than desired for the preparation of the labeled compounds. Such modules are also difficult to modify for the research and development of new compounds and probes. Generally the reactions in such modules take place with reduced efficiency due to the tremendous dilution of reagents necessary for macroscopic liquid handling.
The synthesis of the [F-18]-labeled molecular probe, 2-deoxy-2-[F-18]-fluoro-D-glucose (18F-FDG) is based on three major sequential synthetic processes: (i) Concentration of the dilute [F-18] fluoride solution (1-10 ppm) that is obtained from the bombardment of target water, [O-18]H2O, in a cyclotron; (ii) [F-18]fluoride substitution of the mannose triflate precursor; and (iii) acidic hydrolysis of the fluorinated intermediate. Presently, [F-18]FDG is produced on a routine basis in a processing time (or cycle time) of about 50 minutes using macroscopic commercial synthesizers. These synthesizers consist, in part, of an HPLC pump, mechanical valves, glass-based reaction chambers and ion-exchange columns. The physical size of these units is approximately 80 cm×40 cm×60 cm. Descriptions of macroscopic synthesizers can be found in WO 2007/066089, WO 2005/057589, US 2007/0031492, and US 2004/022696.
Because of the long processing times and low reagent concentrations of macroscopic synthesizers and the short half-life of [F-18]fluorine (t1/2=109.7 min), a considerable decrease in the radiochemical yields of the resulting probe are inevitably obtained. Moreover, because a number of commercialized automation system are constructed for macroscopic synthesis, the process requires the consumption of large amount of valuable reagents (e.g. mannose triflate or other such reagents), which is inefficient and wasteful for performing research at the smaller scale. For example, the required radioactivity for [F-18]FDG PET imaging of a single patient is about 20 mCi, which corresponds to about 240 ng of FDG. However, for small animal imaging applications, such as for a mouse, only about 200 μCi or less of [F-18]FDG is required.
Accordingly, there is a need to develop smaller or miniaturized systems and devices that are capable of processing such small quantities of molecular probes. In addition, there is a need for such systems that are capable of expediting chemical processing to reduce the overall processing or cycle times, simplifying the chemical processing procedures, and at the same time, provide the flexibility to produce a wide range of probes, biomarkers and labeled drugs or drug analogs, inexpensively.
Microfluidic devices can offer a variety of advantages over macroscopic reactors, such as reduced reagent consumption, high concentration of reagents, high surface-to-volume ratios, and improved control over mass and heat transfer. (See, K. Jahnisch, V. Hessel, H. Lowe, M. Baerns, Angew. Chem. 2004, 116: 410-451; Angew. Chem. Int. Ed. Engl. 2004, 43:406-446; P. Watts, S. J. Haswell, Chem. Soc. Rev. 2005, 34:235-246; and G. Jas, A. Kirschning, Chem. Eur. J. 2003, 9:5708-5723.)